Protein-protein interactions represent a new class of exciting drug targets, which are generally considered “undruggable” by conventional small-molecule approaches, because their binding sites are usually large, flat surfaces that lack well defined pockets for small molecules to bind.
Protein-protein interactions (PPIs) are of central importance in essentially all biochemical pathways, including those involved in disease processes. PPIs therefore represent a large class of new, exciting drug targets (Wells, J and McClendon, C. Nature, 2007, 450, 1001-1009). However, PPIs are considered the prototypical “undruggable” or “challenging” targets for the conventional small-molecule approach, because PPIs usually involve large, flat interfaces, with which a small molecule generally does not make enough points of contact to impart high affinity or specificity. On the other hand, it has become relatively straightforward to develop specific, high-affinity antibodies against any protein epitopes including flat surfaces. Non-immunoglobulin protein scaffolds have also been engineered into specific binders to target proteins through library screening and/or in vitro evolution (Koide, A et al. J. Mol. Biol., 1998, 284, 1141-1151; Beste, G et al. Proc. Natl. Acad. Sci. USA, 1999, 96, 1898-1903; Xu, L. H. et al. Chem. Biol., 2002, 9, 933-942; Rutledge, S E et al. J. Am. Chem. Soc., 2003, 125, 1433614347; Steiner, D et al. J. Mol. Biol., 2008, 382, 1211-1227). These antibody and protein binders possess large binding surfaces of their own and are capable of making multiple contacts with a target surface (e.g., those involved in PPIs). Unfortunately, protein-based drugs are impermeable to the mammalian cell membrane; as such they are generally limited to targeting extracellular proteins and are not orally available. Recently, there have been great interests in developing macrocyclic compounds such as cyclic peptides as PPI inhibitors (Koide, A et al. J. Mol. Biol., 1998, 284, 1141-1151; Beste, G et al. Proc. Natl. Acad. Sci. USA, 1999, 96, 1898-1903; Xu, L. H. et al. Chem. Biol., 2002, 9, 933-942; Rutledge, S E et al. J. Am. Chem. Soc., 2003, 125, 1433614347; Steiner, D et al. J. Mol. Biol., 2008, 382, 1211-1227; Dewan, V et al. ACS Chem. Biol., 2012, 7, 761-769; Wu, X et al. Med. Chem. Commun., 2013, 4, 378-382; Tavassoli, A et al. ACS Chem. Biol., 2008, 3, 757-764; Millward, S W et al. ACS Chem. Biol., 2007, 2, 625-634; Zhou, H et al. J. Med. Chem., 2013, 56, 1113-1123; Yamagishi, Y et al. Chem. Biol., 2011, 18, 1562-1570; Ardi, V C et al. ACS Chem. Biol., 2011, 6, 1357-1366; Leduc, A M et al. Proc. Natl. Acad. Sci. USA, 2003, 100, 11273-11278). These macrocycles typically have molecular weights between 500 and 2000 and occupy a largely untapped therapeutic space that is often referred to as the “middle space.” Because of their relatively large sizes and therefore ability to make multiple points of contact with a target, they are able to compete with proteins for binding to flat surfaces, and yet retain many of the pharmacokinetic properties of small molecules. Bicyclic peptides have also been generated in order to further contrain their structures and improve their binding affinity/specificity and metabolic stability (Sun, Y et al. Org. Lett., 2001, 3, 1681-1684; Virta, P and Lonnberg, H J. J. Org. Chem., 2003, 68, 8534; Hennis, C et al. Nat. Chem. Biol., 2009, 5, 502-507; Chen, S et al. ChemBioChem., 2012, 13, 1032-1038; Sako, Y et al. J. Am. Chem. Soc., 2008, 130, 7232-7234; Timmerman, P et al. J. Biol. Chem., 2009, 284, 34126-34134).
Described herein are compounds, compositions, and methods useful for such purposes.